Bone Abstracts

Background: Inherited forms of rickets are metabolic bone diseases developing as a result of inadequate mineralization of a growing bone due to disruption of calcium, phosphorus and/or vitamin D metabolism. Diverse phenotypic presentation and aetiology of these disorders pose difficulties for the diagnosis and management.

Objective and hypotheses: The aim of this study was to perform molecular diagnostics and clinically characterize 137 patients with hereditary forms of rickets.

Method: One hundred and thirty-seven patients were included if they showed clinical and biochemical features compatible with the diagnosis of rickets (namely, low serum calcium and/or phosphate, increased serum levels of alkaline phosphatase, high or normal PTH, and low tubular reabsorption of phosphate). ‘Rickets panel’ genes were sequenced using a custom Ion Ampliseq gene panel and PGM semiconductor sequencer (Ion Torrent). Bioinformatics analysis was performed using Torrent Suite (Ion Torrent) and ANNOVAR (annovar.openbioinformatics.org) software packages.

Results: The study showed that most patients (n=126) were diagnosed with hypophosphatemic rickets (HR), including 66 familial and 60 sporadic cases. The mean age at diagnosis was 7.5 years [0,2;17]. Clinical symptoms of HR included: deformities of leg bones (90%), muscle weakness (75%), multiple dental abscesses (72%) and short stature (52%). The most severe short stature was noted in patients after multiple osteotomies: Me height −3.07 [−3.85; −2.21] (n=42). Mutations were identified in 84% of cases with HR: PHEX (n=106), FGF23 (n=1), CLCN5 (n=1) and SLC34A3 (n=1). In 19 probands no mutations were detected, however, one patient was diagnosed with tumor-induced osteomalacia and two patients had cutaneous skeletal hypophosphatemia syndrome. 11 patients were diagnosed with vitamin D-dependent rickets. In 5 probands mutations were detected in CYP27B1 gene, 3 probands had VDR mutations and in 3 probands no mutations were detected.

Conclusion: The study confirmed predominance of HR caused by PHEX mutations among patients with inherited forms of rickets. Surgery before puberty in patients with HR is associated with a high risk of recurrence of the limb deformity and negative impact on patients’ final height. Early genetic diagnostic helps to start adequate treatment on time, which improves quality of life for patients with inherited forms of rickets.

Disclosure: This work was supported in Alfa-Endo Program of Charities Aid Foundation (CAF) Russia.